A Biomimetic Nanoparticle System Intercepts and Degrades Thrombospondin-1 to Restore Vascular Homeostasis After Ischemic Injury.

The thrombospondin-1 (TSP-1)/CD47 signaling axis plays a critical role in endothelial injury during hepatic ischemia-reperfusion (IR). Targeting this pathway represents a promising strategy to prevent liver IR injury; however, existing CD47 antagonists cause severe hematologic side effects due to nonspecific binding to erythrocytes. This study developed TAX2 (CD47-derived peptide with the sequence CEVSQLLKGDAC)-functionalized biodegradable nanoparticles (TAX2-NPs) that specifically capture TSP-1 and block its interaction with CD47 on liver sinusoidal endothelial cells (LSECs). TAX2-NPs are composed of PLGA and DSPE-PEG-Mal and are conjugated with the cyclic peptide TAX2, derived from the TSP-1-binding domain of CD47. Upon systemic administration, TAX2-NPs preferentially accumulate in the injured liver, where they competitively bind TSP-1, preventing endothelial apoptosis and preserving sinusoidal integrity. Captured TSP-1 is subsequently internalized by macrophages and degraded via the autophagy-lysosome pathway, thereby eliminating residual extracellular TSP-1 and mitigating its prolonged pathogenic effects. Collectively, this study presents a ligand-targeted nanotherapeutic strategy that integrates TSP-1 sequestration, signaling blockade, and autophagy-mediated degradation, offering a safe and effective approach to protect the liver from ischemia-reperfusion injury.